The principal objective of this proposal is to identify the potential role of skin in initiating a protective immune response against Schistosoma mansoni infection in human and mice. The skin is the only site of entry for this parasite into human. It is now well established that in addition to acting as a major physical barrier against invading organisms, the skin functions as an important immunological organ. Therefore, migration of the parasite (schistsosomulae) through various layers of the skin (which lasts for over 48 hrs) should provide ample opportunity for the skin immune system to interact and initiate a T cell (Th1 or Th2 type) response in the skin and its associated lymph nodes. Yet, we know very little of the cutaneous immune responses to schistosomes. Given the fact that skin is also probably the only major site for future vaccination against schistosomiasis in human, it is highly important that we identify and characterize the local responses that might play a crucial role in the generation of protective immune responses. Therefore, in this project we are initially proposing studies that will analyze the immune responses generated in the skin and draining axillary lymph nodes of mice, following infection or immunization. Our preliminary RT-PCR studies show generation of a differential cytokine response in the skin within hours after immunization (IFN-gamma) or infection (IL-4 and IL-10) suggesting that the skin immune system may play a major role in directing the immune responses to appropriate pathways leading to protection or infection. The experiments proposed in this project will further identify the role of various cells in the skin, in initiating this differential response. These studies are thus, important in understanding ways to immunomodulate responses at the local site of immunization or infection in order to generate a strong protective immune response in the host. Our preliminary studies also show that migrating schistosomulae elaborate a low molecular weight factor that modulate the inflammatory and immune response in the skin of mouse and human. Possibly the parasite uses this mechanism to escape immune detection in the skin. Interestingly, schistosomulae of Trichobilharzia ocellata a bird schistosome which induces an acute allergic inflammatory response in the skin (commonly called 'swimmer's itch') do not appear to produce this low molecular weight factor. Therefore, in this study we are also proposing experiments to characterize and clone this factor, develop antibodies and test their ability in potentiating the protective responses. Thus, the studies proposed in this five year project will provide us with clear answers on the (1) role of skin in the generation of a protective immune response against S. mansoni (2) how migrating schistsosomulae escape this mechanism and, (3) possible ways by which we can modulate this response to help predict the success of an immunization protocol.